The HLA complex of man determines two sets of serologically detectable cell surface glycoprotein molecules; the classic histocompatibility or class I antigens which include HLA-A, -B, and -C antigens, and the B cell II antigens, which include the HLA-DR and the newly defined HLA-linked MA, MT and Te antigens. These antigens undoubtedly have a crucial role in regulating the immunologic and immunogenetic phenomena attributed to the HLA complex. Of particular note in this regard is the association of particular diseases with certain HLA antigens. The broad objective of this proposal is to use biochemical techniques to elucidate the fine structure and genetics of HLA-encoded molecules, and to clarify the role of these antigens in disease predisposition. We will internally radiolabel perhpheral blood human lymphocytes and B-cell lymphoblastoid lines with amino acid or carbohydrate precursors. The radiolabeled HLA molecules will be solubilized in non-ionic detergent, immunoprecipitated using alloantisera, and analyzed by 2-dimensional gel electrophoresis, sequential immunoprecipitation, tryptic peptide mapping and partial amino acid sequencing. Using these techniques we will determine whether serologically identical disease-associated HLA antigens differ between patients with the disease and normals with regard to primary protein structure, carbohydrate moieties, and cell surface density. We will ascertain the chemical basis for the closely related antigenic variants or "splits" of HLA class I molecules, and the chemical basis for the cross-reacting groups or CREG's of HLA class I molecules. We will establish whether the MB/MT/Te antigens are borne on the same molecule as the HLA-DR antigens or on a different molecule; whether the molecule bearing a given DR antigen derived from MB/Te positive individuals is different from the molecule bearing the same DR antigen derived from MB/Te negative individuals; whether HLA-DR hybrid molecules exist in HLA-DR heterozygotes, and whether class II molecules derived from activated T lymphocytes are different from their counterparts derived from B cells. In addition, murine monoclonal anti-HLA antibodies will be produced.